Basically substituted cycloalkene compounds as antitussive agents

ABSTRACT

THE ANTITUSSIVE COMPOSITION WHICH COMPRISES SPECIFIC CYCLOALKENE COMPOUNDS AND A PHARMACEUTICAL EXCIPIENT.

United States Patent Int. Cl. A61k 27/00 US. Cl. 424-330 2 Claims ABSTRACT OF THE DISCLOSURE The antitussive composition which comprises specific cycloalkene compounds and a pharmaceutical excipient.

This is a divisional application of Ser. No. 563,044, filed July 6, 1966, now Pat. No. 3,470,249.

The present invention relates to new and valuable cycloalkene compounds and more particularly to cycloalkene compounds of the following Formula I R indicates alkyl containing 1 to 4 carbon atoms and n represents the numerals 0, 1, or 2 wherein and to acid addition salts of said compounds as well as to a process for the manufacture of said compounds.

In Chemical Abstracts vol. 41, page 6253i (1947) there is described the dehydration of l-hydroxy-l-(pmethoxy phenyl)-Z-(dimethylamino methyl) cyclohexane by means of potassium bisulfate. The resulting dehydration product is designated as 1-(p-methoxy phenyl)-Z-(dimethylamino methyl)-1-cyclohexene. It has been found, however, that this compound does not have the structure as assumed, but that it is in fact l-(p-methoxy phenyl)-2- (dimethylamino methyl) 5 cyclohexene. Administering said compound in a dosage up to 2.5 mg. per kg. of cat body weight does not produce any antitussive effect.

It is one object of the present invention to provide new and valuable cycloalkene compounds which have a surprisingly high antitussive activity and which are well tolerated.

Another object of the present invention is to provide a simple and effective process of making such new and valuable cycloalkene compounds.

A further object of the present-invention is to provide valuable antitussive pharmaceutical compositions which can be used in therapy.

Still another object of the present invention is to provide a method of treating coughs and inhibiting or suppressing coughing.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

According to the present invention compounds of Formula I, and especially those in which R indicates a straight chain alkyl, exhibit strong antitussive activity and are generally well tolerated. This is quite surprising since, as stated above, the known l-(p-methoxy phenyl)- Z-(dimethylamino methyl)-5-cyclohexene does not show "ice any such activity at all. For instance, the hydrobromide of l-(m-hydroxy phenyl) 2 (dimethylamino methyl) cyclohexene(1) when administered intravenously to cats in an amount of 1 mg./kg., causes marked inhibition of the mechanically provoked cough reflex in the narcotized cat. A long lasting complete inhibition of this cough reflex is also caused by administration of 1 mg./kg. of the hydrobromide of 1 (m-hydroxy phenyl)-2-(dimethylamino methyl) cycloheptene(1), when administered intravenously to cats.

In addition to said high antitussive activity the compounds of Formula I possess excellent analgesic, antiphlogistic, and antiproliferative activities.

The new componds of Formula I are obtained by reacting a compound of Formula II cm W \CH2N/ OH Nor-12),

wherein CH (jCHzN III wherein R and n have the same meaning as indicated above.

Said intermediate compound is then dehydrated to the corresponding acid addition salt of a compound of Formula I.

The intermediate compounds of Formula III may also be obtained by splitting up the ether group in a compound of Formula II, wherein R for instance, indicates aralkyl, preferably benzyl, by hydrogenolysis.

The resulting intermediate compounds of Formula III are especially useful in the preparation of compounds of Formula I. In this preferred embodiment of the process according to the present invention a compound of Formula III is reacted with dehydrating agents, preferably with formic acid, glacial acetic acid, phosphoric acid, sulfuric acid, or with acid metal salts of said polybasic acids, if required at elevated temperature, and the resulting compound of Formula IV l /CHa "CHr'N wherein R and u have the same meaning as indicated above, is isomerized to a compound of Formula I by the action of aqueous or gaseous hydrogen bromide or by mixtures of hydrobromic acid with suitable acids or solvents, if required, at elevated temperature. The reaction may also be carried out without isolation of the different intermediate compounds.

Using the above mentioned processes for the manufacture of the compounds of Formula I, the salts with hydrobromic acid are obtained. These salts may be used in therapy, it required, after purification. Other acid addition salts of the compounds of Formula I may be prepared by first producing the free bases of Formula I followed by neutralization with the respective acids. Likewise, other acid addition salts of compounds of Formula I are obtained by reacting the hydrobromic acid salts of said compounds with a silver salt, for instance, by reacting the hydrobromide of a compound of Formula I with silver acetate, thereby obtaining the acetic acid salt of the compound of Formula I.

The following examples serve to illustrate the present invention without, however, limiting the same thereto. All temperature data are uncorrected. In carrying out the examples, maximum yields were not intended to be obtained.

EXAMPLE 1 100 g. of l-(m-methoxyphenyl)-2-(dimethylamine methyl) cyclohexanol-(l) are dissolved in a mixture of 400 ml. of glacial acetic acid and 200 ml. of concentrated aqueous hydrobromic acid and the solution is refluxed for 8 hours. The solvent is distilled off under reduced pressure and the residue is dissolved in a mixture of 120 ml. of ethanol and 60 ml. of acetone. On adding ether, 57 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (dimethylamino methyl) cyclohexene(l) are obtained, M.P. 170-472 C.

EXAMPLE 2 15 g. of the hydrochloride of l-(m-hydroxy phenyl)- Z-(dimethylamino methyl)cyclopentanol-(l) are dissolved in 120 ml. of formic acid and the solution is refluxed for 2 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of 50 ml. of ethanol and 25 ml. of acetone. On adding ether, the hydrochloride of l-(m-hydroxy phenyl)-Z-(dimethylamino methyl) cyclopentene-(4) is obtained. 5 g. of said compound are dissolved in a mixture of 50 ml. of glacial acetic acid and 25 ml. of concentrated aqueous hydrobromic acid and the solution is refluxed for 2 hours. The solvent is distilled off. The residue is dissolved in a mixture of ethanol and acetone (2:1). On adding ether,

4.5 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (dimethylamino methyl) cyclopentene(1) are obtained, M.P. 156160 C.

EXAMPLE 3 S g. of the hydrochloride of l-(m-hydroxy phenyl)-2- (dimethylamino methyl) cyclohexanol(1) are dissolved in 50 ml. of formic acid and refluxed for 2 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of 25 ml. of a mixture of ethanol and acetone (2:1). On adding ether, the hydrochloride of 1-(m-hydroxy phenyl) 2 (dimethylamino methyl) cyclohexene-(S) is obtained, M.P. 183184 C. 2 g. of said compound are dissolved in a mixture of 50 ml. of glacial acetic acid and 25 ml. of concentrated aqueous hydrobromic acid and the solution is refluxed for 2 hours. The solvent is distilled off. The residue is dissolved in a mixture of ethanol and acetone. On adding ether, 1.7 g. of the hydrobromide of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cyclohexene(1) are obtained, M.P. 170172 C. The compound is identical with that of Example 1.

EXAMPLE 4 43 g. of the hydrochloride of l-(m-hydroxy phenyl)- Z-(dimethylamino methyl) cycloheptanol-(l) are dis- 4 solved in 200 ml. of formic acid and the solution is refluxed for 2 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of ml. of ethanol and 25 ml. of acetone. On adding ether, the hydrochloride of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cycloheptene-(6) is obtained, M.P. 193-197 C. 15 g. of said compound are dissolved in a mixture of 50 ml. of glacial acetic acid and 25 ml. of concentrated aqueous hydrobromic acid and the solution is refluxed for 3 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in ml. of a mixture of ethanol and acetone (2:1). On adding ether, 17 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (dimethylamino methyl) cycloheptene(1) are obtained, M.P. l58-160 C.

EXAMPLE 5 11 g. of the hydrochloride of l-(m-hydroxyl phenyl)- Z-(methyl-n-propylamino methyl) cyclohexanol-(l) are dissolved in 150 ml. of formic acid and the solution is refluxed for 2 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of 50 ml. of ethanol and 25 ml. of acetone. On adding ether, the hydrochloride of l-(m-hydroxy phenyl)-2- methyl-n-propylamino methyl) cyclohexene-(S) is obtained, M.P. 133135 C. 3 g. of said compound are dissolved in a mixture of 40 ml. of glacial acetic acid and 20 ml. of concentrated aqueous hydrobromic acid and the solution is refluxed for 3 hours. The solvent is distilled off under reduced pressure. The residue is dis solved in 30 ml. of a mixture of ethanol and acetone (2:1). On adding ether, 1.8 g. of the hydrobromide of 1- (m-hydroxy phenyl -2-meth yl-n-propylamino methyl) cyclohexene(l) are obtained, M.P. 122l26 C.

EXAMPLE 6 14.3 g. of the hydrochloride of l-(m-hydroxy phenyl)- Z-(methyl ethylamino methyl) cycloheptanol-(l) are dissolved in 170 ml. of formic acid and the solution is refluxed for 2 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of ml. of glacial acetic acid and 40 ml. of concentrated aqueou hydrobromic acid and the solution is refluxed for 3 hours. The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of ethanol and acetone (2:1). On adding ether, the hydrobromide of l-(m-hydroxy phenyl)-Z-(methyl ethylamino methyl) cycloheptene(1) is obtained, M.P. 11912l C.

The cycloalkanols used as starting materials in Examples 2 to 6, are obtained as follows:

EXAMPLE 7 (a) 11.0 g. of magnesium turnings are treated, while stirring with a solution of 87.5 g. of m-bromo phenyl benzyl ether in 250 ml. of absolute tetrahydrofuran at such a rate that the reaction mixture boils gently because of the heat produced by the reaction which starts immediately. Thereafter, the reaction mixture is boiled under reflux, while stirring, until all the magnesium is dissolved. The reaction mixture is cooled to 0 C. to l0 C. and a mixture of 47 g. of Z-dimethylamino methyl cyclopentanone and ml. of absolute tetrahydrofuran is added dropwise thereto. The resulting mixture is stirred at room temperature for 4 hours and then poured into a saturated aqueous solution of ammonium chloride. The resulting layers are separated from each other and the aqueous layer is extracted twice with 50 ml. portion of ether. The organic layers are combined, dried with sodium sulfate and evaporated. The residue is distilled whereby l-(mbenzoxy phenyl)-Z-(dimethylamino methyl) cyclopentanol-(l), boiling at 189195 C./0.009 mm. Mg. is obtained. 30 g. of said compound are dissolved in 200 m1. of absolute ethanol. After adding palladium precipitated on charcoal, the compound i hydrogenated at atmospheric pressure. The catalyst is filtered off. On adding a solution of hydrogen chloride in ether to the filtrate, the hydrochloride of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cyclopentanol-(l) is obtained, M.P. 198-201" C.

By reacting 'm-benzyloxy phenyl magnesium bromide with the respective basic ketone and by hydrogenolysis of the intermediate compound in the same manner as described hereinabove, the following compounds are obtained. i

(b) l-(m-benzoxy phenyl)-2-d1methylamino methyl) cyclohexanol-(l), boiling at 156-160 C./ 0.003 mm. Hg.

Hydrochloride of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cyclohexanol-(l), melting point: 208- 210 C.

(c) l-(mabenzoxy phenyl) 2 (dimethylamino methyl) cycloheptanol-(l), boiling at 19.5 C./0.005 mm. Hg.

Hydrochloride of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cycloheptanol-(l), M.P. 204-205 C.

(d) l-(m-benzoxy phenyl)-2-(methyl-n-propylamino methyl) cyclohexanol-(l), boiling at 205-215 C./.001 mm. Hg.

Hydrochloride of l-(m-hydroxy phenyl)-2-(methyl-npropylamino methyl) cyclohexanol-(l), M.P. 182-184 C (e) 1 (m benzoxy phenyl 2 (methyl ethylamino methyl) cycloheptanol-(l), boiling at 195 C./ 0.0001 mm. Hg.

Hydrochloride of l-(m-hydroxy phenyl)-2-(rnethylethylamino methyl) cycloheptanol-(l), M.P. 175-176 C.

EXAMPLE 8 2 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (dimethylamino methyl)cyclohexene(1) are dissolved in 25 ml. of water and an excess of an aqueous solution of sodium hydrogen carbonate is added thereto. The mixture is extracted three times with ether, the combined extracts are dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene. On adding petroleum ether, 1-(mhydroxy phenyl)-2-(dimethylamino methyl) cyclohexene(l) is obtained in the form of white crystals, M.P. 101-103 C.

EXAMPLE 9 1 g. of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cyclohexenefl) is dissolved in a mixture of 10 ml. of a mixture of ethanol and acetone (2:1). On adding a solution of hydrogen chloride in ether thereto, the hydrochloride of l-(rn-hydroxy phenyl)-2-(dimethylamino methyl) cyclohexene(1) is obtained, M.P. 176 178 C.

In place of the basically substituted cycloalkanols used in the preceding examples, there may be employed other basically substituted cycloalkanol such as l-(m-hydroxy phenyl)-2-(methyl-n-butylamino methyl) cyclopentanol- (1), cyclohexanol-(l), or cycloheptanol-(l), l-(m-hydroxy phenyl)-2-(methyl-n-propylamino methyl) cyclopentanol-(l) or cycloheptanol-(l), or '1-in(m-hydroxy phenyl)-2-(methyl ethylamino methyl) cyclopentanol-( 1) or cycloheptanol-(l), while otherwise the procedure is the same as described in the preceding examples.

Other acid addition salts than the hydrobromides and hydrochloride described in the preceding examples such as the acid addition salts with other pharmaceutically acceptable inorganic acids, for instance, with sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, or with substantially non-toxic, pharmaceutically acceptable organic acids, for instance, with acetic acid, propionic acid, maleic acid, succinic acid, gluconic acid, malic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, acetyl salicylic acid, phthalic acid, ni-cotinic acid, isonicotinic acid, furan-Z-c-arboxylic acid, and others may be prepared according to the methods described hereinbefore or by other suitable methods.

The new basically substituted cyc1oalkene-(1) compounds of Formula I and their pharmaceutically acceptable acid addition salts can be administered orally,

parenterally or rectally. Compositions containing said active compounds as used in therapy comprise, for instance, tablets, pills, drages, lozenges, and the like shaped preparations to be administered orally. The active compounds may also be administered in powder form, preferably enclosed in gelatin or the like capsules. Oral adminstration in liquid form, such as in the form of solutions, emulsions, suspensions, sirups, and the like is also possible. Such solid and liquid preparations are produced in a manner known to the art of compounding and processing pharamaceutical products whereby the conventional diluting, binding, and/or expanding agents, lubricants, and/ or other excipents, such as lactone, cane sugar, dextrins, starch, talc, kaolin, magnesium hydroxide, magnesium carbonate, pectin, gelatin, agar, bentonite, stearic acid, magnesium stearate, and others may be employed.

The following examples serve to illustrate the preparation of pharmaceutical compositions as they are used in therapy, without, however, limiting the same thereto.

EXAMPLE 10 Tablets 20 g. of the hydrobromide of l-(rn-hydroxy phenyl)-2- (dirnethylamino methyl) cyclohexene(1), 50.56 g. of microcrystalline cellulose, 75.84 g. of spray-dried lactose, 12 g. of dried corn starch, and 1.6 g. of magnesium stearate are intimately mixed with each other and are compressed, without preceding granulation, to tablets of 7 mm. diameter and a weight of mg. Each tablet contains 20 mg. of the active compound.

EXAMPLE 11 Drages The mixture of ingredients described in example 10 is compressed to biconvex drages cores of 160 mg. each.

These cores are sugar-coated by rotating in a coating pan with sugar sirup. Each drage contains 20- mg. of the hydrobromide of l-(m-hydroxy phenyl)-2-dimethylamino methyl) cyclohexene(1) EXAMPLE 12 Capsules 20 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (dimethylamino methyl) cyc10heptene( 1), 161.2 g. of anhydrous di-basic calcium phosphate (-U.S.Ph.), 6.6 g. of parafiinum perliquidum (3rd supplement to D.A.B.6), and 2.2 g. of magnesium stearate are intimately mixed and the mixture is sieved. Portions of mg. each of said mixture are filled in gelatin capsules. Each capsule contains 20 mg. of the active compound.

EXAMPLE l3 Suppositories 117 g. of a suppository base (corresponding to adeps solidun, 3rd supplement to D.A.B. 6) and 2 g. of the hydrobromide of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cyclohexene(1) are thoroughly triturated while warming the suppository base. The mixture is cast into suppository molds, each of which contains 1.19 g. of the mixture, and is cooled to cause solidification. Each suppository contains 20 mg. of the active com-pound.

EXAMPLE 14 Sirup 0.4 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (dimethylamino methyl) cyclohexene(1), 0.5 g. of sodium carboxy methyl cellulose, 0.2 0 g. of the potassium salt of sorbic acid, 0.3 g. of the sodium salt of cyclohexane sulfamic acid, 1.03 g. of saccharin sodium, 20 g. of sugar, 1.4 g. of tinctura aurantia dulcis, 0.7 g. of polysorbate 80, and 0.01 g. of a certified color are intimately mixed with each other, dissolved in distilled water, and

made up to a volume of 100 cc. cc. of the resulting sirup contains 20 mg. of the active compound.

EXAMPLE Pharmaceutical drops 2 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (methyl ethylamino methyl) cycloheptene(1) are intimately mixed with 0.1 g. of saccharin sodium, 3.5 g. of the sodium salt of cyclohexane sulfamic acid. 0.1 g. of sorbic acid, 30.0 g. of 96% ethanol, 0.3 g. of polysorbate 80, and 0.3 g. of peppermint spirit. The mixture is dissolved in distilled water and made up to a volume of 100 cc. One cc. of said solution contains mg. of the active compound.

EXAMPLE 16 Injectable solution 0.5 g. of the hydrobromide of l-(m-hydroxy phenyl)-2- (dimethylamino methyl) cyclohexene(l) and 2.0 of sodium citrate are dissolved in 200 cc. of water. Each cc. of the resulting solution contains 2.5 mg. of the active compound. The solution is filtered to free it of fibers and is filled into ampoules which are then sterilized by heating to 120 C. The solution is administered by intramuscular injection.

Compositons as described in the preceding examples have been adminstered to patients suffering from bronchial asthma which in some of them was of chronic nature. Administration of 20 mg. of the hydrobromide of l-(mhydroxy phenyl) 2 (dimethylamino methyl) cyclohexene(1), for instance, suppressed the cough reflex completely within a short period of time regardless whether adminstered in the form of tablets, capsules, drages, or drops.

Patients suffering from pneumonia, some of them from chronic pneumonia, received 20 mg. of the hydrochloride of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cyclohexene(l) to suppress nocturnal coughing. Rapid onset of relief was observed.

Complete and prolonged suppression of coughing was achieved by administering 20 mg. of the hydrobromide of l-(m-hydroxy phenyl)-2-(dimethylamine methyl) cyclohexene(l) to a patient with a plasmosytoma.

Carcinoma patients, especially patients suffering from bronchial carcinoma could be relieved from coughing by administration of 20 mg. of the hydrobromide of l-(mhydroxy phenyl)-2-(dimethylamino methyl)cyclohexene (1).

A patient suffering from lung congestion accompanied by cardiac insutficiency received 20 mg. of the hydrobromide of l-(m-hydroxy phenyl)-2-(dimethylamino methyl) cyclohexene(l) to suppress nocturnal coughing. Rapid onset of the cough suppressing elfect was observed.

Of course, many changes and variations in the starting materials, the reactants, dehydrating and isomerizing agents, the solvents used, the reaction conditions, temperature, and duration, the acids used for forming the acid addition salts, the method of isolating and purifying the antitussive agents of the present invention and their pharmaceutically acceptable acid addition salts, the pharmaceutical compositions containing said antitussive agents and their salts, the mode of administration, and

the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

We claim:

1. An antitussive composition comprising an effective antitussive amount of a cycloalkene(l) compound selected from the group consisting of a cycloalkene(l) compound of the formula IIO-Q /CH3 mamas wherein R indicates alkyl having 1 to 4 carbon atoms and n represents the numerals 0, 1, and 2,

and pharmaceutically acceptable acid addition salts of said cycloalkene 1) compound.

References Cited UNITED STATES PATENTS 11/1962 Green 260570.8 1/1963 Huebner 260570.8X

OTHER REFERENCES Barrett et al.: Jour. Chem. Soc., London, 1958, pages 340-8.

Lee et al.: Chemical Abstracts, vol. 41, pages 6246-54 (1947 Royals: Advanced Organic Chemistry, pages 3l2-3, (1954).

Wagner et al.: Synthetic Organic Chemistry, pages 32- 35 (1953).

JEROME D. GOLDBERG, Primary Examiner 

